This application seeks funding for studies aimed at dissecting how the self-ligand cell surface receptor Ly108 (Slamf6) controls the adaptive and innate immune responses involved in the pathogenesis of experimental colitis. Studies with genetically well-defined mouse models of experimental IBD lead to an understanding that perturbations of the finely tuned balance between the immune system and the vast antigenic load of the colon results in disease. We are beginning to dissect how Treg cells prevent colitis, inducing pathogenic CD4+ T cells, e.g. Th1, Th2 or Th17, from expanding in the lamina propria. However, we do not understand many of the genetic and mechanistic networks that are implicated in the regulation of innate and adaptive immune responses to bacterial antigens and/or mouse antigens induced by colonic bacteria. Our general hypothesis is that the receptor isoforms encoded by the autoimmune gene Ly108, i.e. Ly108-1, Ly108-2 and Ly108-H1, govern distinct pathways to colitis. As our Preliminary Studies will demonstrate: i) engagement of Ly108 ameliorates colitis; ii) Ly108 governs distinct CD4+ T cell and NKT cell responses; and iii) Ly108 modulates responses to bacteria by macrophages or neutrophils, most likely because Ly108 enters phagosomes as a scavenger-receptor. The fundamental strategy is to dissect the consequences of an imbalance of the three isoforms of Ly108 in T cell and phagocyte responses to commensal bacteria and in the pathogenesis of experimental colitis. We have the systems in place to employ our large series of novel genetically altered mice, our monoclonal antibodies, and soluble ligands to demonstrate the importance of receptor isoform interplay in disease manifestations. The proposed experiments are grouped into the following specific aims: Specific Aim #1: To test the hypothesis that the three isoforms of Ly108 initiate distinct responses by CD4+ T cells. Specific Aim #2: To test the hypothesis that Ly108 controls microbicidal mechanisms in mouse dendritic cells, macrophages and neutrophils. Specific Aim #3: To determine the role of Ly108 on the surface of T cells and phagocytes in the pathogenesis of experimental colitis.